Pancreas cancer is an extremely lethal disease with the lowest 1-year and 5-year survival rates of any cancer. This is due, in part, to the extremely metastatic behavior of pancreas carcinoma cells, which are also highly resistant to therapy. Importantly, we now know that invasive pancreas cancer most commonly arises from precursor lesions, termed pancreatic intraepithelial neoplasms (PanINs), but can also arise from the less common mucinous cystic neoplasms (MCNs). Somewhat perplexing is the fact that cystic neoplasms have a dramatically improved prognosis even through both neoplasms involve mutations in the same cardinal oncogenes and tumor suppressor genes. Importantly, in both pathologies, a strong, but nevertheless unique, stromal response is present, which is highly relevant as it is now recognized that, in many solid tumors, the local microenvironment and the stromal compartment significantly influences disease progression. In conventional pancreatic ductal adenocarcinoma, and its most common precursor PanIN lesions, disease progression is associated with a robust fibrotic response in the stroma, or desmoplastic reaction, that is largely regulated by pancreatic stellate cells. Likewise, the stroma of MCNs is also characterized by excess extracellular matrix deposition, but also demonstrates "ovarian-type" features characterized by densely packed, wavy, spindle shaped stellate cells that can be estrogen and progesterone positive. Furthermore, in culture, stellate cells are known to secrete factors that can promote cell behaviors associated with tumor progression, suggesting a paracrine signaling role for stellate cells in vivo, However, to date, the molecular mechanisms by which pancreatic stellate cells regulate epithelial carcinoma cell behavior in vivo are not well understood. Therefore, here, using murine models of pancreas cancer that faithfully mimics the human disease, we propose specific experiments to explicitly investigate the role of stromal stellate cells in preinvasive and invasive disease. We hypothesize that pancreatic stellate cells promote carcinoma progression and that these cells are co-opted in early PanIN lesions help drive conversion to invasive carcinoma. Furthermore, we hypothesize that stellate cells co-opted in PanIN lesions more robustly promote carcinoma progression than their counterparts in MCN lesions, consistent with the dramatically different temporal progression of these two routes to invasive adenocarcinoma. PUBLIC HEALTH RELEVANCE: Pancreas cancer kills every patient it afflicts. It is now the fourth leading cause of cancer-related deaths in this country with a rising incidence and unabated mortality. We have developed genetically engineered animal models of pancreas cancer that have exposed unique points of vulnerability for the development of new treatments. We propose a systematic program of investigation the role of stromal pancreatic stellate cells in pancreas cancer progression and identify novel therapeutic targets that can ultimately improve survival.